DESCRIPTION Musculoskeletal injuries affect over 28 million patients in the United States each year, in both the civilian and military populations. Analysis of casualty data suggests that a high number of injuries sustained in combat may require restoration of structures such as the flexor tendon, rotator cuff and Achilles tendon. Unfortunately, these structures have a poor healing capacity, thought to be due in part to the large amount of inflammation during the first several weeks following repair. Historically, clinicians have prescribed non-steroidal anti-inflammatories (NSAIDs) after tendon repair to reduce pain and inflammation but recent studies suggest that these drugs may be detrimental to the healing process. Contrastingly, one study showed improved healing after a delayed delivery of NSAIDs, suggesting that perhaps some inflammation is necessary for beginning the appropriate wound healing cascade but that early and sustained inflammation could be detrimental to tissue remodeling. Therefore, the objective of this study is to investigate the effect of NSAIDs in the early phases of repair on tendon healing by studying both a dose and time dependent delivery of NSAIDs. We hypothesize that local delivery of NSAIDs by release from a microsphere-laden scaffold will have a more pronounced effect on tendon repair mechanical properties than delivery via oral gavage. Additionally, we hypothesize that a late delivery (7-14 days) of the drugs will improve healing while early delivery (0-7 days) will inhibit healing. The hypotheses will be evaluated using a clinically relevant rat model of rotator cuff injury in a degenerative tendon in conjunction with or novel nanofibrous scaffold-microsphere composite delivery system. Assessment of the tensile mechanical properties of the tendons as well as collagen organization, cellularity, cell shape, fibril morphology and the presence of inflammatory cells, could help to deduce the specific mechanisms by which NSAID delivery affects tendon healing. This proposal will specifically address this uncertainty by assessing the delivery of NSAIDs both locally and systemically. Augmentation of the repair combined with concurrent drug delivery in this manner could enhance long-term tendon healing and limit inflammation following rotator cuff repair. In addition, determining a better solution to pain management following musculoskeletal tissue repair, such as delayed NSAID delivery, could help to avoid medications that lead to high morbidity, such as opioids and narcotics.